The present invention relates to nor-seco himbacine derivatives useful as thrombin receptor antagonists in the treatment of diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, cerebral ischemia, stroke, neurodegenerative diseases and cancer. Thrombin receptor antagonists are also known as protease activated receptor (PAR) antagonists. The compounds of the invention also bind to cannabinoid (CB2) receptors and are useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis. The invention also relates to pharmaceutical compositions containing said compounds.
Thrombin is known to have a variety of activities in different cell types and thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. It is therefore expected that thrombin receptor antagonists will be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
Thrombin receptor antagonist peptides have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bernatowicz et al, J. Med. Chem., 39 (1996), p. 4879-4887, tetra- and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2 and N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NH2. Peptide thrombin receptor anatgonists are also disclosed in WO 94/03479, published Feb. 17, 1994.
Cannabinoid receptors belong to the superfamily of G-protein coupled receptors. They are classified into the predominantly neuronal CB1 receptors and the predominantly peripheral CB2 receptors. These receptors exert their biological actions by modulating adenylate cyclase and Ca+2 and K+ currents. While the effects of CB1 receptors are principally associated with the central nervous system, CB2 receptors are believed to have peripheral effects related to bronchial constriction, immunomodulation and inflammation. As such, a selective CB2 receptor binding agent is expected to have therapeutic utility in the control of diseases associated with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis (R. G. Pertwee, Curr. Med. Chem. 6(8), (1999), 635).
Himbacine, a piperidine alkaloid of the formula 
has been identified as a muscarinic receptor antagonist. The total synthesis of (+)-himbacine is disclosed in Chackalamannil et al, J. Am. Chem Soc., 118 (1996), p. 9812-9813.
Tricyclic himbacine-related compounds have been disclosed as thrombin receptor antagonists in U.S. Pat. No. 6,063,847.
The present invention relates to thrombin receptor antagonists represented by the formula I 
or a pharmaceutically acceptable salt thereof, wherein:
Z is xe2x80x94(CH2)nxe2x80x94; 
wherein R10 is absent; or 
wherein R3 is absent;
the single dotted line represents an optional double bond;
the double dotted line represents an optional single bond;
n is 0-2;
R1 and R2 are independently selected from the group consisting of H, C1-C6 alkyl, fluoro(C1-C6)alkyl, difluoro(C1-C6)alkyl, trifluoro-(C1-C6)alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, aryl(C1-C6)alkyl, aryl(C2-C6)alkenyl, heteroaryl(C1-C6)alkyl, heteroaryl(C2-C6)alkenyl, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, amino-(C1-C6)alkyl, aryl and thio(C1-C6)alkyl; or R1 and R2 together form a xe2x95x90O group;
R3 is H, hydroxy, C1-C6 alkoxy, xe2x80x94NR18R19, xe2x80x94SOR16, xe2x80x94SO2R17, xe2x80x94C(O)OR17, xe2x80x94C(O)NR18R19, C1-C6 alkyl, halogen, fluoro(C1-C6)alkyl, difluoro(C1-C6)alkyl, trifluoro(C1-C6)alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, aryl(C1-C6)alkyl, aryl(C2-C6)alkenyl, heteroaryl(C1-C6)alkyl, heteroaryl(C2-C6)alkenyl, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, aryl, thio(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkylamino(C1-C6)alkyl;
R34 is (H, R3), (H, R43), xe2x95x90O or xe2x95x90NOR17 when the optional double bond is absent; R34 is R44 when the double bond is present;
Het is a mono-, bi- or tricyclic heteroaromatic group of 5 to 14 atoms comprised of 1 to 13 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein a ring nitrogen can form an N-oxide or a quaternary group with a C1-C4 alkyl group, wherein Het is attached to B by a carbon atom ring member, and wherein the Het group is substituted by 1 to 4 substituents, W, independently selected from the group consisting of H; C1-C6 alkyl; fluoro(C1-C6)alkyl; difluoro(C1-C6)alkyl; trifluoro-(C1-C6)-alkyl; C3-C7 cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted by C1-C6 alkyl, C2-C6 alkenyl, OHxe2x80x94(C1-C6)alkyl, or xe2x95x90O; C2-C6 alkenyl; R21-aryl(C1-C6)alkyl; R21-aryl-(C2-C6)-alkenyl; R21-aryloxy; R21-aryl-NHxe2x80x94; heteroaryl(C1-C6)alkyl; heteroaryl(C2-C6)-alkenyl; heteroaryloxy; heteroaryl-NHxe2x80x94; hydroxy(C1-C6)alkyl; dihydroxy(C1-C6)alkyl; amino(C1-C6)alkyl; (C1-C6)alkylamino-(C1-C6)alkyl; di-((C1-C6)alkyl)-amino(C1-C6)alkyl; thio(C1-C6)alkyl; C1-C6 alkoxy; C2-C6 alkenyloxy; halogen; xe2x80x94NR4R5; xe2x80x94CN; xe2x80x94OH; xe2x80x94COOR17; xe2x80x94COR16; xe2x80x94OSO2CF3; xe2x80x94CH2OCH2CF3; (C1-C6)alkylthio; xe2x80x94C(O)NR4R5; xe2x80x94OCHR6-phenyl; phenoxy-(C1-C6)alkyl; xe2x80x94NHCOR16; xe2x80x94NHSO2R16; biphenyl; xe2x80x94OC(R6)2COOR7; xe2x80x94OC(R6)2C(O)NR4R5; (C1-C6)alkoxy; xe2x80x94C(xe2x95x90NOR17)R18; C1-C6 alkoxy substituted by (C1-C6)alkyl, amino, xe2x80x94OH, COOR17, xe2x80x94NHCOOR17, xe2x80x94CONR4R5, aryl, aryl substituted by 1 to 3 substutuents independently selected from the group consisting of halogen, xe2x80x94CF3, C1-C6 alkyl, C1-C6 alkoxy and xe2x80x94COOR17, aryl wherein adjacent carbons form a ring with a methylenedioxy group, xe2x80x94C(O)NR4R5 or heteroaryl;
R21-aryl; aryl wherein adjacent carbons form a ring with a methylenedioxy group;
R41-heteroaryl; and heteroaryl wherein adjacent carbon atoms form a ring with a C3-C5 alkylene group or a methylenedioxy group;
R4 and R5 are independently selected from the group consisting of H, C1-C6 alkyl, phenyl, benzyl and C3-C7 cycloalkyl, or R4 and R5 together are xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94 or xe2x80x94(CH2)2NR7xe2x80x94(CH2)2xe2x80x94 and form a ring with the nitrogen to which they are attached;
R6 is independently selected from the group consisting of H, C1-C6 alkyl, phenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(Cl-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl and amino(C1-C6)alkyl;
R7 is H or (C1-C6)alkyl;
R8, R10 and R11 are independently selected from the group consisting of R1 and xe2x80x94OR1, provided that when the optional double bond is present, R10 is absent;
R9 is H, OH, C1-C6 alkoxy, halogen or halo(C1-C6)alkyl;
B is xe2x80x94(CH2)n3xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94CH2xe2x80x94NR6xe2x80x94, xe2x80x94C(O)NR6xe2x80x94, xe2x80x94NR6C(O)xe2x80x94, 
cis or trans xe2x80x94(CH2)n4CR12xe2x95x90CR12a(CH2)n5 or xe2x80x94(CH2)n4Cxe2x89xa1C(CH2)n5xe2x80x94, wherein n3 is 0-5, n4 and n5 are independently 0-2, and R12 and R12a are independently selected from the group consisting of H, C1-C6 alkyl and halogen;
X is xe2x80x94Oxe2x80x94 or xe2x80x94NR6xe2x80x94 when the double dotted line represents a single bond, or X is H, xe2x80x94OH or xe2x80x94NHR20 when the bond is absent;
Y is xe2x95x90O, xe2x95x90S, (H, H), (H, OH) or (H, C1-C6 alkoxy) when the double dotted line represents a single bond, or when the bond is absent, Y is xe2x95x90O, xe2x95x90NOR17, (H, H), (H, OH), (H, SH), (H, C1-C6 alkoxy) or (H, xe2x80x94NHR45);
R15 is absent when the double dotted line represents a single bond; R15 is H, C1-C6 alkyl, xe2x80x94NR18R19 or xe2x80x94OR17 when the bond is absent; or Y is 
or 
and R15 is H or C1-C6 alkyl;
R16 is C1-C6 lower alkyl, phenyl or benzyl;
R17, R18 and R19 are independently selected from the group consisting of H, C1-C6 alkyl, phenyl, benzyl;
R20 is H, C1-C6 alkyl, phenyl, benzyl, xe2x80x94C(O)R6 or xe2x80x94SO2R6;
R21 is 1 to 3 substutuents independently selected from the group consisting of hydrogen, xe2x80x94CF3, xe2x80x94OCF3, halogen, xe2x80x94NO2, C1-C6 alkyl, C1-C6alkoxy, (C1-C6)alkylamino, di-((C1-C6)alkyl)amino, amino(C1-C6)alkyl, (C1-C6)-alkylamino(C1-C6)alkyl, di-((C1-C6)alkyl)-amino(C1-C6)alkyl, hydroxy-(C1-C6)alkyl, xe2x80x94COOR17, xe2x80x94COR17, xe2x80x94NHCOR16, xe2x80x94NHSO2R16, xe2x80x94NHSO2CH2CF3, heteroaryl or xe2x80x94C(xe2x95x90NOR17)R18;
R22 and R23 are independently selected from the group consisting of hydrogen, R24xe2x80x94(C1-C10)alkyl, R24xe2x88x92(C2-C10)alkenyl, R24xe2x80x94(C2-C10)alkynyl, R27-hetero-cycloalkyl, R25-aryl, R25-aryl(C1-C6)alkyl, R29xe2x80x94(C3-C7)cycloalkyl, R29xe2x80x94(C3-C7)cycloalkenyl, xe2x80x94OH, xe2x80x94OC(O)R30, xe2x80x94C(O)OR30, xe2x80x94C(O)R30, xe2x80x94C(O)NR30R31, xe2x80x94NR30R31, xe2x80x94NR30C(O)R31, xe2x80x94NR30C(O)NR31R32, xe2x80x94NHSO2R30, xe2x80x94OC(O)NR30R31, R24xe2x80x94(C1-C10)alkoxy, R24xe2x80x94(C2-C10)-alkenyloxy, R24xe2x80x94(C2-C10)alkynyloxy, R27-heterocycloalkyloxy, R29xe2x80x94(C3-C7)cycloalkyloxy, R29xe2x80x94(C3-C7)cyclo-alkenyloxy, R29xe2x80x94(C3-C7)cycloalkyl-NHxe2x80x94, xe2x80x94NHSO2NHR16 and xe2x80x94CH(xe2x95x90NOR17);
or R22 and R10 together with the carbon to which they are attached, or R23 and R11 together with the carbon to which they are attached, independently form a R42-substituted carbocyclic ring of 3-10 atoms, or a R42-substituted heterocyclic ring of 4-10 atoms wherein 1-3 ring members are independently selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 and xe2x80x94SO0-2xe2x80x94, provided that when R22 and R10 form a ring, the optional double bond is absent;
R24 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, halogen, xe2x80x94OH, (C1-C6)alkoxy, R35-aryl, (C1-C10)-alkyl-C(O)xe2x80x94, (C2-C10)-alkenyl-C(O)xe2x80x94, (C2-C10)alkynyl-C(O)xe2x80x94, heterocycloalkyl, R26xe2x80x94(C3-C7)cycloalkyl, R26xe2x80x94(C3-C7)cycloalkenyl, xe2x80x94OC(O)R30, xe2x80x94C(O)OR30, xe2x80x94C(O)R30, xe2x80x94C(O)NR30R31, xe2x80x94NR30R31, xe2x80x94NR30 C(O)R31, xe2x80x94NR30C(O)NR31R32, xe2x80x94NHSO2R30, xe2x80x94OC(O)NR30R31, R24xe2x80x94(C2-C10)-alkenyloxy, R24xe2x80x94(C2-C10)alkynyloxy, R27-heterocycloalkyloxy, R29xe2x80x94(C3-C7)-cycloalkyloxy, R29xe2x80x94(C3-C7)cyclo-alkenyloxy, R29xe2x80x94(C3-C7)cycloalkyl-NHxe2x80x94, xe2x80x94NHSO2NHR 16 and xe2x80x94CH(xe2x95x90NOR17);
R25 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, heterocycloalkyl, halogen, xe2x80x94COOR36, xe2x80x94CN, xe2x80x94C(O)NR37R38, xe2x80x94NR39C(O)R40, xe2x80x94OR36, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-C1-C6)alkyl, (C1-C6)alkyl(C3-C7)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl(C3-C7)cycloalkyl(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, and R41-heteroaryl; or two R25 groups on adjacent ring carbons form a fused methylenedioxy group
R26 is 1, 2, or 3 substituents independently selected from the group consisting of hydrogen, halogen and (C1-C6)alkoxy;
R27 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, R28xe2x80x94(C1-C10)alkyl, R28xe2x80x94(C2-C10)alkenyl, R28xe2x80x94(C2-C10)alkynyl,
R28 is hydrogen, xe2x80x94OH or (C1-C6)alkoxy;
R29 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, (C1-C6)alkyl, xe2x80x94OH, (C1-C6)alkoxy and halogen;
R30, R31 and R32 are independently selected from the group consisting of hydrogen, (C1-C10)-alkyl, (C1-C6)alkoxy(C1-C10)-alkyl, R25-aryl(C1-C6)-alkyl, R33xe2x80x94(C3-C7)cycloalkyl, R34xe2x88x92(C3-C7)cycloalkyl(C1-C6)alkyl, R25-aryl, heterocycloalkyl, heteroaryl, heterocycloalkyl(C1-C6)alkyl and heteroaryl(C1-C6)alkyl;
R33 is hydrogen, (C1-C6)alkyl, OHxe2x80x94(C1-C6)alkyl or (C1-C6)alkoxy;
R35 is 1 to 4 substituents independently selected from the group consisting of hydrogen, (C1-C6)alkyl, xe2x80x94OH, halogen, xe2x80x94CN, (C1-C6)alkoxy, trihalo(C1-C6)alkoxy, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, xe2x80x94OCF3, OHxe2x80x94(C1-C6)alkyl, xe2x80x94CHO, xe2x80x94C(O)(C1-C6)-alkylamino, xe2x80x94C(O)di((C1-C6)alkyl)amino, xe2x80x94NH2, xe2x80x94NHC(O)(C1-C6)alkyl and xe2x80x94N((C1-C6)alkyl)C(O)(C1-C6)alkyl;
R36 is hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, dihalo(C1-C6)alkyl or trifluoro(C1-C6)alkyl,
R37 and R38 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl and (C3-C15)cycloalkyl, or R37 and R38 together are xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94 or xe2x80x94(CH2)2xe2x80x94NR39xe2x80x94(CH2)2xe2x80x94 and form a ring with the nitrogen to which they are attached;
R39 and R40 are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl and (C3-C15)-cycloalkyl, or R39 and R40 in the group xe2x80x94NR39C(O)R40, together with the carbon and nitrogen atoms to which they are attached, form a cyclic lactam having 5-8 ring members;
R41 is 1 to 4 substituents independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, xe2x80x94OCF3, OHxe2x80x94(C1-C6)alkyl, xe2x80x94CHO and phenyl;
R42 is 1 to 3 substituents independently selected from the group consisting of hydrogen, xe2x80x94OH, (C1-C6)alkyl and (C1-C6)alkoxy;
R43 is xe2x80x94NR30R31, xe2x80x94NR30C(O)R31, xe2x80x94NR30 C(O)NR31R32, xe2x80x94NHSO2R30 or xe2x80x94NHCOOR17;
R44 is H, C1-C6 alkoxy, xe2x80x94SOR16, xe2x80x94SO2R17, xe2x80x94C(O)OR17, xe2x80x94C(O)NR18R19, C1-C6 alkyl, halogen, fluoro(C1-C6)alkyl, difluoro(C1-C6)alkyl, trifluoro(C1-C6)alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, aryl(C1-C6)alkyl, aryl(C2-C6)alkenyl, heteroaryl(C1-C6)alkyl, heteroaryl(C2-C6)alkenyl, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, aryl, thio(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkylamino(C1-C6)alkyl; and
R45 is H, C1-C6 alkyl, xe2x80x94COOR16 or xe2x80x94SO2.
R2, R8, R10 and R11 are each preferably hydrogen. R3 preferably is hydrogen, OH, C1-C6 alkoxy, xe2x80x94NHR18 or C1-C6 alkyl. The variable n is preferably zero. R9 is preferably H, OH or alkoxy. R1 is preferably C1-C6 alkyl, more preferably methyl. The double dotted line preferably represents a single bond; X is preferably xe2x80x94Oxe2x80x94 and Y is preferably xe2x95x90O or (H, xe2x80x94OH). B is preferably trans xe2x80x94CHxe2x95x90CHxe2x80x94. Het is preferably pyridyl, substituted pyridyl, quinolyl or substituted quinolyl. Preferred substituents (W) on Het are R21-aryl, R41-heteroaryl or alkyl. More preferred are compounds wherein Het is 2-pyridyl substituted in the 5-position by R21-aryl, R41-heteroaryl or alkyl, or 2-pyridyl substituted in the 6-position by alkyl. R34 is preferably (H,H) or (H,OH).
R22 and R23 are preferably selected from OH, (C1-C10)alkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, trifluoro(C1-C10)alkyl, trifluoro(C2-C10)-alkenyl, trifluoro(C2-C10)alkynyl, (C3-C7)-cycloalkyl, R25-aryl, R25-aryl(C1-C6)alkyl, R25-arylhydroxy(C1-C6)alkyl, R25-aryl-alkoxy-(C1-C6)alkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, (C1-C10)alkoxy, (C3-C7)cycloalkyloxy, (C1-C6)alkoxy(C1-C6)alkyl, OHxe2x80x94(C1-C6)alkyl, trifluoro(C1-C10)alkoxy and R27-heterocycloalkyl(C1-C6)alkyl. More preferred are compounds wherein R22 and R23 are independently selected from the group consisting of (C1-C10)alkyl and OHxe2x80x94(C1-C6)alkyl.
Thrombin receptor antagonist compounds of the present invention have anti-thrombotic, anti-platelet aggregation, antiatherosclerotic, antirestenotic and anti-coagulant activity. Thrombosis-related diseases treated by the compounds of this invention are thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic and thromboembolytic stroke, peripheral vascular diseases, other cardiovascular diseases, cerebral ischemia, inflammatory disorders and cancer, as well as other disorders in which thrombin and its receptor play a pathological role.
The compounds of the invention which bind to cannabinoid (CB2) receptors are useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis.
This invention also relates to a method of using a compound of formula I in the treatment of thrombosis, platelet aggregation, coagulation, cancer, inflammatory diseases or respiratory diseases, comprising administering a compound of formula I to a mammal in need of such treatment. In particular, the present invention relates to a method of using a compound of formula I in the treatment of thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, cerebral ischemia, cancer, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, reversible airway obstruction, chronic asthma or bronchitis. It is contemplated that a compound of this invention may be useful in treating more than one of the diseases listed.
In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in a pharmaceutically acceptable carrier.
Unless otherwise defined, the term xe2x80x9calkylxe2x80x9d or xe2x80x9clower alkylxe2x80x9d means straight or branched alkyl chains of 1 to 6 carbon atoms and xe2x80x9calkoxyxe2x80x9d similarly refers to alkoxy groups having 1 to 6 carbon atoms.
Fluoroalkyl, difluoroalkyl and trifluoroalkyl mean alkyl chains wherein the terminal carbon is substituted by 1, 2 or 3 fluoroatoms, e.g., xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CHF2 or xe2x80x94CH2CH2F. Haloalkyl means an alkyl chain substituted by 1 to 3 halo atoms.
xe2x80x9cAlkenylxe2x80x9d means straight or branched carbon chains of carbon atoms having one or more double bonds in the chain, conjugated or unconjugated. Similarly, xe2x80x9calkynylxe2x80x9d means straight or branched carbon chains of carbon atoms having one or more triple bonds in the chain. Where an alkyl, alkenyl or alkynyl chain joins two other variables and is therefore bivalent, the terms alkylene, alkenylene and alkynylene are used. Unless otherwise defined, alkenyl and alkynyl chains comprise 1 to 6 carbon atoms.
Substitution on alkyl, alkenyl and alkynyl chains depends on the length of the chain, and the size and nature of the substituent. Those skilled in the art will appreciate that while longer chains can accommodate multiple substituents, shorter alkyl chains, e.g., methyl or ethyl, can have multiple substitution by halogen, but otherwise are likely to have only one or two substituents other than hydrogen. Shorter unsaturated chains, e.g., ethenyl or ethynyl, are generally unsubstituted or substitution is limited to one or two groups, depending on the number of available carbon bonds.
xe2x80x9cCycloalkylxe2x80x9d means a saturated carbon ring of 3 to 7 carbon atoms, while xe2x80x9ccycloalkylenexe2x80x9d refers to a corresponding bivalent ring, wherein the points of attachment to other groups include all positional and stereoisomers. xe2x80x9cCycloalkenylxe2x80x9d refers to a carbon ring of 3 to 7 atoms and having one or more unsaturated bonds, but not having an aromatic nature.
xe2x80x9cHeterocycloalkylxe2x80x9d means saturated rings of 5 or 6 atoms comprised of 4 to 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NR7xe2x80x94 joined to the rest of the molecule through a carbon atom. Examples of heterocycloalkyl groups are 2-pyrrolidinyl, tetrahydrothiophen-2-yl, tetrahydro-2-furanyl, 4-piperidinyl, 2-piperazinyl, tetrahydro-4-pyranyl, 2-morpholinyl and 2-thiomorpholinyl.
xe2x80x9cHalogenxe2x80x9d refers to fluorine, chlorine, bromine or iodine radicals.
When R4 and R5 join to form a ring with the nitrogen to which they are attached, the rings formed are 1-pyrrolidinyl, 1-piperidinyl and 1-piperazinyl, wherein the piperazinyl ring may also be substituted at the 4-position nitrogen by a group R7.
xe2x80x9cDihydroxy(C1-C6)alkylxe2x80x9d refers to an alkyl chain substituted by two hydroxy groups on two different carbon atoms.
xe2x80x9cArylxe2x80x9d means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.
xe2x80x9cHeteroarylxe2x80x9d means a single ring or benzofused heteroaromatic group of 5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. N-oxides of the ring nitrogens are also included, as well as compounds wherein a ring nitrogen is substituted by a C1-C4 alkyl group to form a quaternary amine. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. Examples of benzofused heteroaryl groups are indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (i.e., thionaphthenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. W-substituted heteroaryl refers to such groups wherein substitutable ring carbon atoms have a substituent as defined above, or where adjacent carbon atoms form a ring with an alkylene group or a methylenedioxy group, or where a nitrogen in the Het ring can be substituted with R21-aryl or an optionally substituted alkyl substituent as defined in W.
The term xe2x80x9cHetxe2x80x9d is exemplified by the single ring and benzofused heteroaryl groups as defined immediately above, as well as tricyclic groups such as benzoquinolinyl (e.g., 1,4 or 7,8) or phenanthrolinyl (e.g., 1,7; 1,10; or 4,7). Het groups are joined to group B by a carbon ring member, e.g., Het is 2-pyridyl, 3-pyridyl or 2-quinolyl.
Examples of heteroaryl groups wherein adjacent carbon atoms form a ring with an alkylene group are 2,3-cyclopentenopyridine, 2,3-cyclohexenopyridine and 2,3-cycloheptenopyridine.
The term xe2x80x9coptional double bondxe2x80x9d refers to the bond shown by the single dotted line in the middle ring of the structure shown for formula I. The term xe2x80x9coptional single bondxe2x80x9d refers to the bond shown by the double dotted line between X and the carbon to which Y and R15 are attached in the structure of formula I.
The above statements, wherein, for example, R4 and R5 are said to be independently selected from a group of substituents, means that R4 and R5 are independently selected, but also that where an R4 or R5 variable occurs more than once in a molecule, those occurrences are independently selected. Those skilled in the art will recognize that the size and nature of the substituent(s) will affect the number of substituents which can be present.
Compounds of the invention have at least one asymmetrical carbon atom and therefore all isomers, including diastereomers and rotational isomers are contemplated as being part of this invention. The invention includes (+)- and (xe2x88x92)-isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of formula I.
Typical preferred compounds of the present invention have the following stereochemistry: 
with compounds having that absolute stereochemistry being more preferred.
Those skilled in the art will appreciate that for some compounds of formula I, one isomer will show greater pharmacological activity than other isomers.
Compounds of the invention with a basic group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention.
Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, lithium, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Compounds of the present invention are generally prepared by processes known in the art, for example by the processes described below.
Compounds of formula IA, wherein n is 0, the optional double bond is not present, the single bond is present between X and the carbon to which Y is attached, X is xe2x80x94Oxe2x80x94, Y is xe2x95x90O, B is xe2x80x94CHxe2x95x90CHxe2x80x94, Het is W-substitued pyridyl, R3, R8, R9, R10 and R11 are each hydrogen, and R1 and R2 are as defined above can be prepared by condensing an aldehyde of formula II, wherein the variables are as defined above, with a phosphonate of formula III, wherein W is as defined above: 
Similar processes may be used to prepare compounds comprising other optionally substituted Het groups. Those skilled in the art will also recognize that the processes are equally applicable to preparing optically active or racemic compounds.
Compounds of formula IA can be converted to the corresponding compounds wherein R3 is OH by treatment with Davis reagent ((1S)-(+)-(10-camphorsulfonyl)-oxaziridine) and LHMDS (Lithium bis(trimethylsilyl)amide).
Aldehydes of formula II can be prepared from dienoic acids, for example compounds of formula IIa, wherein R1 is H and R2 is methyl can be prepared according to the following reaction scheme. 
The alkyne of formula 4, prepared by known methods, is esterified with the dienoic acid of formula 3 using standard conditions to yield the ester 5. Selective reduction of the triple bond of 5 using Lindlar catalyst under hydrogen gives the intermediate 6, which upon thermal cyclization at about 185xc2x0 C., followed by base treatment, gives the intermediate 7. The ester 7 is subjected to hydrogenation in the presence of platinum oxide to generate the intermediate saturated carboxylic acid, treatment of which with oxalyl chloride gives the corresponding acid chloride which is converted to the aldehyde IIa by reduction using tributyltin hydride in the presence of Palladium catalyst.
Dienoic acids of formula 3 are commercially available or are readily prepared.
Aldehydes of formula II also can be prepared by a thiopyran ring opening, for example compounds of formula IIa as defined above can be prepared according to the following reaction scheme. 
The alkyne of formula 4, is reduced to the alkene 13 using Lindlar catalyst under hydrogen. The alkene 13 is esterified with the dienoic acid of formula 12 using standard conditions to yield the ester 14. Thermal cyclization at about 185xc2x0 C., followed by base treatment, gives the intermediate 15. The ester 15 is converted to the intermediate carboxylic acid, and the double bond is reduced by hydrogenation in the presence of a platinum catalyst. The acid is then treated with oxalyl chloride to obtain the corresponding acid chloride, which is converted to the aldehyde 18 by reduction using tributyltin hydride in the presence of Palladium catalyst. The aldehyde moiety on 18 is treated with a reducing agent such as NaBH4, and the sulfur-containing ring is then opened by treatment with a reagent such as Raney nickel to obtain the alcohol 19. The alcohol is then oxidized to the aldehyde, IIa, using tetrapropylammonium perruthenate (TPAP) in the presence of 4-methylmorpholine N-oxide (NMO).
Phosphonates of formula III wherein W is aryl or R21-aryl can be prepared by a process similar to that described immediately below for preparing the trifluoromethy-phenyl-substituted compound, IIIa. 
Commercially available hydroxypyridine derivative is converted to the corresponding triflate using triflic anhydride, which is then coupled with commercially available boronic acid in the presence of Pd(0) under Suzuki conditions. The resulting product is converted to the phosphonate by treatment with n-butyllithium followed by quenching with diethylchlorophosphonate.
Alternatively, compounds of formula I wherein W is optionally substituted aryl can be prepared from compounds of formula I wherein W is xe2x80x94OH using a triflate intermediate. For example, 3-hydroxy-6-methylpyridine is treated with triisopropylsilyl chloride, and the resultant hydroxy-protected compound is converted to the phosphonate as described above for preparing intermediate IIIa. The triisopropylsilyl-protected intermediate is then reacted with intermediate II and the protecting group is removed under standard conditions. The resultant compound of formula I wherein W is OH is then treated with triflic anhydride at room temperature in a solvent such as CH2Cl2; the triflate is then reacted with an optionally substituted arylboronic acid, e.g., optionally substituted phenylboronic acid, in a solvent such as toluene, in the presence of Pd(PPh3)4 and a base such a K2CO3 at elevated temperatures and under an inert atmosphere.
Compounds of formula I wherein W is a substituted hydroxy group (e.g., benzyloxy) can be prepared from compounds of formula I wherein W is hydroxy by refluxing in a suitable solvent such as acetone with a halogen-substituted compound such as optionally substituted benzyl bromide in the presence of a base such as K2CO3.
Compounds of formula I wherein Het is substituted by W through a carbon atom (e.g., wherein W is alkyl, alkenyl or arylalkyl) or a nitrogen atom (i.e., xe2x80x94NR4R5) can be prepared as shown in Scheme 3 using a compound of formula I wherein W is chloroalkyl as an intermediate. Compounds of formula I wherein W is a polar group such as hydroxy alkyl, dihydroxyalkyl, xe2x80x94COOH, dimethylamino and xe2x80x94COH can be prepared as shown in Scheme 4, wherein the starting material is a compound of formula I wherein W is alkenyl. The following Schemes 3 and 4 show well-known reaction conditions for preparing various W-substituted compounds wherein X is xe2x80x94Oxe2x80x94, Y is xe2x95x90O, R15 is absent, R1 is methyl, R2, R3, R9, R10 and R11 are each H, B is xe2x80x94CHxe2x95x90CHxe2x80x94, and Het is 2-pyridyl. 
Those skilled in the art will appreciate that similar reactions to those described in the above schemes may be carried out on other compounds of formula I as long as substituents present would not be susceptible to the reaction conditions described.
Compounds of formula I wherein the optional single bond (represented by the double dotted line) is absent, X is OH, Y is OH, R15 is H and the remaining variables are as defined above can be prepared by treating corresponding compounds wherein the optional single bond is present, X is xe2x80x94Oxe2x80x94, Y is xe2x95x90O and R15 is absent, with a reducing agent such as LAH.
Compounds of formula I wherein the optional single bond is present, X is xe2x80x94Oxe2x80x94, Y is (H, OH), R15 is absent and the remaining variables are as defined above can be prepared by treating corresponding compounds wherein the optional single bond is present, X is xe2x80x94Oxe2x80x94, Y is xe2x95x90O and R15 is absent, with a reagent such as DIBAL. The resultant compounds wherein Y is (H, OH) can be converted to the corresponding compounds wherein Y is (H, alkoxy) by reacting the hydroxy compound with an appropriate alkanol in the presence of a reagent such as BF3.OEt2. A compound wherein Y is (H, OH) can also be converted to the corresonding compound wherein Y is (H, H) by treating the hydroxy compound with BF3.OEt2 and Et3SiH in an inert solvent such as CH2Cl2 at low temperatures.
Compounds of formula I wherein R9 is hydrogen can be converted to the corresponding compound wherein R9 is hydroxy by heating with an oxidizing agent such as SeO2.
Compounds of formula IB, wherein R2 is H, R3 is H or OH, and W1 is R21-aryl, R41-heteroaryl, amino or hydroxylamino derivatives, are prepared from compounds of formula 1A wherein W is 5-bromo (compounds of formula 23 or 24) using a variety of standard chemical transformations, e.g. the Suzuki reaction, Stille coupling, and Buchwald amination. Reaction Scheme 5 shows the process from the 2,5-dibromopyridine: 
The phosphonate 22 is prepared from the known alcohol 21 by a two step transformation: the alcohol is treated with CH3SO2Cl to provide the mesylate, which is then displaced with sodium diethylphosphite to provide 22. Intermediate 23 can also be xcex1-hydroxylated using Davis reagent to provide alcohol 24. Both 23 and 24 can be converted into diverse analogs as shown in Scheme 6: 
A shown in Scheme 6, the bromide (23 or 24) can be coupled with boronic acids under palladium catalysis condition (method 1). If the boronic acid possesses a functional group, it can be subsequently transformed. Similarly, aryl-tin compounds (method 2), aryl-zinc compounds (method 3) and amines (method 4) can be coupled. Heck reaction with vinyl ethers can introduce a keto-group, which can be subsequently functionalized (method 5). Imidazoles can be coupled using Copper(I) triflate as catalyst (method 6). The bromide can also be converted to a cyanide which can be subsequently transformed, for example to a tetrazole (method 7).
Using a Diels-Alder strategy as shown in Scheme 7, a variety of dienoic acids 3 can be coupled with alcohol 25 and the ester 26 can be subjected to thermal cyclization to provide the Diels-Alder product IC: 
Alcohol 25 is prepared from the readily available (R)-(+)-3-butyn-2-ol 27. The alcohol is protected as its TBDPS ether, the alkyne is deprotonated and quenched with paraformaldehyde to provide alcohol 29. The alkyne is reduced to cis-alkene using Lindlar catalyst in presence of quinoline and the allylic alcohol was oxidized to provide the aldehyde 30, which is converted to the alcohol 25.
Compounds of formula ID wherein R22 is xe2x80x94CH2OC(O)CH3 or a derivative thereof, R23 is ethyl, R2 is H and the remaining variables are as defined for IA can be prepared from the corresponding tetrahydropyran analog by opening the ring. The compounds of formula ID can be converted to other compounds of formula I, e.g. compounds of formula IE wherein R22 is xe2x80x94CH2OH, by well known methods. The reaction is shown in Scheme 8: 
Tetrahydropyran analog 31 can be prepared starting from 3-formyl-5,6-dihydro-2H-pyran (known compound) and using the similar procedure used in Scheme 1. The ring can opened regioselectively using BBr3 and the alcohol can be protected to give the acetate ID. Bromide reduction with NaCNBH3, followed by acetate deprotection, furnishes alcohol IE.
Starting materials for the above processes are either commercially available, known in the art, or prepared by procedures well known in the art.
Reactive groups not involved in the above processes can be protected during the reactions with conventional protecting groups which can be removed by standard procedures after the reaction. The following Table A shows some typical protecting groups:
The present invention also relates to a pharmaceutical composition comprising a compound of formula I of this invention and a pharmaceutically acceptable carrier. The compounds of formula I can be administered in any conventional oral dosage form such as capsules, tablets, powders, cachets, suspensions or solutions. The formulations and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques. Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.
The daily dose of a compound of formula I for treatment of a disease or condition cited above is about 0.001 to about 100 mg/kg of body weight per day, preferably about 0.001 to about 10 mg/kg. For an average body weight of 70 kg, the dosage level is therefore from about 0.1 to about 700 mg of drug per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
Following are examples of preparing starting materials and compounds of formula I. In the procedures, the following abbreviations are used: room temperature (rt), tetrahydrofuran (THF), ethyl ether (Et2O), methyl (Me), ethyl (Et), ethyl acetate (EtOAc), dimethylformamide (DMF), 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,3-dicyclohexylcarbodiimide 
Step 1: 
See J. Org. Chem., 59 (17) (1994), p. 4789.
Step 2: 
To a suspension of 60% NaH (7.42 g,185.5 mmol, 1.3 eq) in 300 ml THF at 0xc2x0 C. was added dropwise triethylphosphono acetate (37 ml, 186.5 mmol, 1.3 eq) and the mixture was stirred at 0xc2x0 C. for 30 min. The product of Step 1 (14.0 g, 142.7 mmol) was added and the mixture was stirred at 0xc2x0 C. for 30 min. The reaction was quenched by the addition of aq. NH4Cl (500 ml), the THF was evaporated and the aqueous phase was extracted with 3xc3x97200 ml of Et2O, the combined organic layer was washed with brine (300 ml), dried over MgSO4, filtered and evaporated to give the crude mixture which was chromatographed (5% Et2O-hexane) to give 18.38 g (77% yield) of liquid.
1H NMR (400 MHz, CDCl3) 7.29 (d, 1H, J=15.4), 5.86 (t, 1H, J=7.4), 5.76 (d, 1H, J=15.4), 4.18 (q, 2H, J=7.2), 2.22-2.15 (m, 2H), 1.74 (d, 3H, J=0.7), 1.27 (t, 3H, J=7.2), 1.00 (t, 3H, J=7.7) 13C NMR (100 MHz, CDCl3) 167.29, 149.38, 143.45, 132.04, 115.39, 60.08, 22.14, 14.42, 13.58, 12.05 MS: 169 (MH+)
Step 3: 
To a solution of the product of Step 2 (6.4 g, 38 mmol) in THF and MeOH (40 ml each) was added a solution of KOH (6.4 g, 114 mmol, 3 eq) in H2O (40 ml). The mixture was stirred at rt for 2 h, cooled to 0xc2x0 C. and H2O (100 ml) and 1N HCl (150 ml) were added. The mixture was extracted with EtOAc (3xc3x97100 ml), the combined organic layer was washed with H2O (150 ml) and brine (150 ml), dried over MgSO4, filtered and evaporated to give 5.26 g (99% yield) of crystalline solid.
1H NMR (400 MHz, CDCl3) 7.40 (d, 1H, J=16), 5.95 (t, 1H, J=7.2), 5.79 (d, 1H, J=16), 2.26-2.19 (m, 2H), 1.78 (s, 3H), 1.04 (t, 3H, J=7.6)
Step 4: 
To a solution of the product of Step 3 (2.0 g, 14.3 mmol) in CH2Cl2 (70 ml) was added oxalyl chloride (2.5 ml, 28.7 mmol, 2 eq.) followed by DMF (33 xcexcl, 3 mol %.). The mixture was stirred at rt for 1 h, then the solvent was evaporated to give the crude acid chloride which was dissolved in CH2Cl2 (70 ml) and cooled to 0xc2x0 C. To this was added DMAP (175 mg, 1.43 mmol, 0.1 eq.) and a solution of alcohol 4 (2.62 g, 12.8 mmol, 0.9 eq.)in CH2Cl2 (5 ml) followed by Et2N (4 ml, 28.7 mmol, 2 eq.). The mixture was stirred at 0xc2x0 C. for 2 h, diluted with Et2O (200 ml), washed with aq. NaHCO3 and brine (200 ml each), and dried over MgSO4. The solution was filtered, concentrated and the resultant residue was chromatographed with 5% EtOAc-hexane to provide 3.56 g (85%) of pale-yellow resin.
1H NMR (400 MHz, CDCl3) 7.38-7.33 (m, 6H), 5.93 (t, 1H, J=7.4), 5.77 (d, 1H, J=15.6), 5.62 (q, 1H, J=6.2), 5.20 (s, 2H), 2.25-2.18 (m, 2H), 1.76 (d, 3H, J=0.4), 1.58 (d, 3H, J=6.2), 1.03 (t, 3H, J=7.4)
Step 5: 
To a solution of the product of Step 4 (3.19 g, 9.8 mmol) in THF (50 ml) was added Lindlar catalyst (320 mg, 10 wt %) and quinoline (230 xcexcl, 2.0 mmol, 0.2 eq.). The suspension was stirred under 1 atm. H2 until the starting material was consumed. The solution was filtered through celite and evaporated. The resin was dissolved in EtOAc (250 ml) and washed with 1N HCl (3xc3x97100 ml) and brine (100 ml). The solution was dried over MgSO4, filtered and evaporated to give 3.17 g of crude alkene which was used directly in the next step.
Step 6: 
A solution of the product of Step 5 (3.15 g, 9.6 mmol) in m-xylene (100 ml) was heated at 185xc2x0 C. for 10 h. The solution was cooled to rt and stirred for 1 h with DBU (290 xcexcl, 1.94 mmol, 0.2 eq.). The solvent was evaporated and the crude was chromatographed with 10% EtOAc-hexane to provide 1.1 g (35%) of exo product. 1H NMR (400 MHz, CDCl3) 7.38-7.34 (m, 5H), 5.45 (br s,1 H), 5.14 (ABq, J=12.0, 22.8, 2H), 4.52 (dq, J=6.1, 8.1, 1H), 3.26-3.23 (m, 1H), 2.87 (dd, J=9.4, 4.6, 1H), 2.62 (dt, J=8.1, 4.5, 1H), 2.54 (br s, 1H), 1.71 (t, J=1.2, 3H), 1.69-1.60 (m, 1H), 1.50-1.44 (m, 1H), 1.20 (d, J=6.4, 3H), 0.77 (t, J=7.4, 3H) 13C NMR (100 MHz, CDCl3) 175.25, 173.04, 137.86, 135.00, 128.38, 128.34, 128.30, 116.54, 76.64, 66.70, 42.85, 42.14, 41.40, 37.27, 22.52, 21.65, 20.44, 8.98 [xcex1]22D=xe2x88x9264.4 (c 1, CH2Cl2) HRMS: 329.1754, calculated 329.1753
Step 7: 
To a solution of the product of Step 6 (1.35 g, 4.1 mmol) in EtOAc (30 ml) was added 10% Pd-C (140 mg, 10 wt %) and the suspension was stirred under H2 balloon for 5 h. The mixture was filtered through celite and concentrated. The crude material was dissolved in MeOH (30 ml), PtO2 (100 mg) was added and the mixture was shaken in a Parr vessel at 50 Psi H2 for 2 days. The mixture was filtered through celite and evaporated to give 980 mg (99%) of the acid as foam.
1H NMR (400 MHz, CDCl3) 4.73-4.66 (m, 1H), 2.71 (dd, J=11.8, 5.4, 1H), 2.68-2.62 (m, 1H), 2.53 (dt, J=10.0, 6.4, 1H), 1.92, ddd, J=13.4, 6.0, 2.6, 1H), 1.63-1.57 (m, 1H), 1.52-1.20 (unresolved m, 3H), 1.30(d, J=5.9, 3H), 0.96 (d, J=6.6, 3H), 0.93-0.89 (m, 1H), 0.80 (t, J=7.5, 3H) MS: 319.1 (MH+.DMSO)
Step 8:
To a solution of the product of Step 7 (490 mg, 2.04 mmol) in CH2Cl2 (20 ml) was added oxalyl chloride (360 xcexcl, 4.13 mmol, 2 eq.) followed by 1 drop of DMF. The solution was stirred at rt for 1 h and the solvent was removed to provide the crude acid chloride, which was dissolved in toluene (20 ml) and cooled to 0xc2x0 C. To this was added Pd(PPh3)4 (236 mg, 0.20 mmol, 0.1 eq.) followed by Bu3SnH (825 xcexcl, 3.07 mmol, 1.5 eq.). The mixture was stirred for 3 h at 0xc2x0 C., concentrated and chromatographed with 25% EtOAc-hexane to provide the title compound 220 mg (48%) as a resin.
1H NMR (400 MHz, CDCl3) 9.72 (d, J=3.6, 1H), 4.70 (dq, J=5.7, 9.5, 1H), 2.71-2.64 (m, 2H), 2.56-2.51 (m, 1H), 1.98 (ddd, J=13.5, 6.1, 2.9, 1H), 1.68-1.59 (m, 3H), 1.52-1.37 (m, 1H), 1.36 (d, J=5.9, 3H), 1.32-1.20 (m, 1H), 1.00 (d, J=6.2, 3H), 0.80 (d, J=7.3, 3H) 
Step 1: 
The thiopyran enal was prepared according to the procedure of McGinnis and Robinson, J. Chem. Soc., 404 (1941), 407.
Step 2: 
To a suspension of 60% NaH (6.3 g, 158 mmol, 1.3 eq.) in THF (200 ml) at 0xc2x0 C. was added methyl diethylphosphonoacetate (29 ml, 158 mmol, 1.3 eq.) and the mixture was stirred at 0xc2x0 C. for 30 min. The solution was then transferred to a solution of the product of Step 1 (15.6 g, 122 mmol) in THF (100 ml) and stirred at 0xc2x0 C. for 1 h. The reaction was quenched by the addition of aq. NH4Cl (500 ml) and the THF was evaporated. The aqueous phase was extracted with Et2O (3xc3x97200 ml) and the combined organic layer was washed with H2O and brine (200 ml each). The solution was dried over MgSO4, concentrated and the resultant residue was chromatographed with 5% EtOAc-hexane to provide 13.0 g (58%) of oil. 1H NMR (400 MHz, CDCl3) 7.26 (d, J=15.9 Hz, 1H), 6.26 (t, J=4.4 Hz, 1H), 5.78 (dd, J=15.9, 0.6 Hz, 1H), 3.75 (s, 3H), 3.25-3.23 (m, 2H), 2.71 (t, J=5.8 Hz, 2H), 2.57-2.53 (m, 2H).
Step 3: 
To a solution of the product of Step 2 (13.0 g, 70.6 mmol) in THF and MeOH (50 ml each) was added a solution of KOH (11.9 g, 212 mmol, 3.0 eq.) in H2O (50 ml). The mixture was stirred at rt for 1 h, diluted with H2O (100 ml) and acidified with 1N HCl. The aqueous phase was extracted with EtOAc (3xc3x97200 ml) and the combined organic layer was washed with H2O and brine (300 ml each). The solution was dried over MgSO4, filtered and evaporated to give 11.66 g (97%) of pale-yellow solid. 1H NMR (400 MHz, CDCl3) 7.34 (d, J=15.6 Hz,1H), 6.32 (t, J=4.4 Hz,1H), 5.78 (d, J=15.6 Hz, 1H), 3.26 (d, J=1.6 Hz, 2H), 2.72 (t, J=5.8 Hz, 2H), 2.59-2.55 (m, 2H).
Step 4: 
To a solution of 4 (5.2 g) in EtOAc (120 ml) was added Lindlar catalyst (520 mg) and the suspension was stirred under 1 atm. H2. Another portion of catalyst (500 mg) was added after 45 min. and the mixture stirred for further 30 min. The mixture was filtered through a celite pad and evaporated to provide 5.2 g (99%) of the desired alkene. 1H NMR (400 MHz, CDCl3) 7.38-7.26 (m, 5H), 6.32 (dd, J=11.9, 6.6 Hz, 1H), 5.86 (d, J=12.0 Hz, 1H), 5.18 (s, 2H), 5.12-5.07 (m, 1H), 3.20 (br s,1H), 1.34 (d, J=6.6 Hz, 3H).
Step 5: 
To a solution of the product of Step 3 (2.45 g, 14.39 mmol) in CH2Cl2 (60 ml) at 0xc2x0 C. was added DCC (3.27 g, 15.85 mmol, 1.1 eq.) followed by DMAP (352 mg, 2.88 mmol, 0.2 eq.) and the mixture was stirred at 0xc2x0 C. for 30 min. To this was added a solution of 3.27 g (15.85 mmol, 1.1 eq.) of the alcohol of Step 4 in 10 ml of CH2Cl2 and the mixture was stirred at 0xc2x0 C. for 5 hr and at rt for 1 hr. The solution was diluted with 350 ml of Et2O and washed with 2xc3x97200 ml of aq. citric acid, 200 ml of aq. NaHCO3 and 200 ml of brine. The solution was dried over MgSO4, filtered, concentrated and the resultant residue was chromatographed with 6% EtOAc-hex to provide 2.1 g (41%) of resin. 1H NMR (400 MHz, CDCl3) 7.38-7.32 (m, 5H), 7.45 (d, J=16.0 Hz, 1H), 6.38-6.34 (m, 1H), 6.26 (t, J=4.6 Hz, 1H), 6.21 (d, J=11.6 Hz, 1H), 6.19 (d, J=11.2 Hz, 1H), 5.85 (dd, J=11.6, 1.2 Hz, 1H), 5.76 (d, J=16.0 Hz, 1H), 5.18 (d, J=1.2 Hz, 2H), 3.24 (d, J=2.0 Hz, 2H), 2.71 (t, 2H, J=5.6 Hz, 2H), 2.56-2.52 (m, 2H), 1.41 (d, J=6.4 Hz, 3H)
Step 6: 
A solution of the product of Step 5 (2.1 g, 5.85 mmol) in m-xylene (50 ml) was heated at 200xc2x0 C. for 6 h in sealed tube. The solution was cooled to rt and stirred with DBU (178 xcexcl, 1.19 mmol, 0.2 eq.) for 1 h, concentrated and chromatographed with 15% EtOAc-hexane to provide 1.44 g (69%) of the desired exo product. 1H NMR (400 MHz, CDCl3) 7.39-7.35 (m, 5H), 5.46 (br s,1H), 5.16 (ABq, J=21.6, 12.0 Hz, 2H), 4.42 (dq, J=9.2, 6.0 Hz,1H), 3.36-3.33 (m 2H), 3.08 (dd, J=14.4, 2.4 Hz,1H), 2.85 (ddd, J=13.9, 12.4, 2.5 Hz,1H), 2.72-2.57 (m, 4H), 2.27-2.21 (m,1H), 1.47-1.25 (m, 1H), 1.12 (d, J=6.4 Hz, 3H)
Step 7: 
To a solution of the product of Step 6 (750 mg, 2.09 mmol) in CH2Cl2 (10 ml) at xe2x88x9278xc2x0 C. was added BBr3 in CH2Cl2 (4.2 ml of 1M solution). The solution was stirred at xe2x88x9278xc2x0 C. for 30 min. and at 0xc2x0 C. for 30 min, then poured into aq. K2CO3 (100 ml). The aqueous phase washed with Et2O (2xc3x9750 ml) and the organic layer was back extracted with aq. K2CO3 (50 ml). The combined aqueous phase was acidified with 1N HCl and extracted with EtOAc (3xc3x9750 ml). The EtOAc layer was washed with brine (50 ml), dried over MgSO4, filtered and evaporated to provide 500 mg (89%) of acid. 1H NMR (400 MHz, CDCl3) 5.50 (br s, 1H), 4.47 (dq, J=9.6, 6.0 Hz, 1H), 3.43-3.39 (m, 1H), 3.36 (d, J=15.6 Hz, 1H), 3.10 (dd, J=14.0, 2.4 Hz, 1H), 2.91-2.84 (m, 1H), 2.82-2.77 (m, 1H), 2.70 (dd, J=10.6, 4.2 Hz, 1H), 2.69-2.63 (m, 1H), 2.57-2.52 (m, 1H), 2.34-2.29 (m, 1H), 1.53-1.42 (m, 1H), 1.34 (d, J=6.0 Hz, 3H).
Step 8: 
To a solution of the product of Step 7 (500 mg, 1.86 mmol) in MeOH (30 ml) was added AcOH (3 ml) and PtO2 (250 mg) and the suspension was shaken under 40 Psi H2 in a Parr vessel for 1.5 days. The catalyst was filtered off with a celite pad, the solution was concentrated and the resultant residue was dissolved in AcOHxe2x80x94MeOHxe2x80x94CH2Cl2 mixture (0.5:2:97.5 v/v/v/) and filtered through a short SiO2 column to provide 400 mg (79%) of the reduced product as a resin which solidified on standing. 1H NMR (400 MHz, CDCl3) 4.68 (dq, J=9.4, 5.9 Hz, 1H), 2.76-2.69 (m, 2H), 2.60-2.55 (m, 3H), 2.49 (d, J=11.6 Hz, 1H), 2.10 (br s, 1H), 1.93 (ddd, J=13.5, 6.0, 2.7 Hz, 1H), 1.60-1.48 (m, 2H), 1.45-1.19 (m, 3H), 1.33 (d, J=5.6 Hz, 3H).
Step 9: 
To a solution of the product of Step 8 (97 mg, 0.36 mmol) in CH2Cl2 (4 ml) was added oxalyl chloride (94 xcexcl) followed by 1 drop of DMF. The solution was stirred for 1 h at rt and concentrated to provide the crude acid chloride which was dissolved in toluene (3 ml) and cooled to 0xc2x0 C. Pd(PPh3)4 (42 mg, 0.04 mmol, 0.1 eq.) was added, followed by Bu3SnH (94 xcexcl). The mixture was stirred at 0xc2x0 C. for 3 h, concentrated and chromatographed with 25% EtOAc-hexane to provide 73 mg (80%) of aldehyde as white solid. 1H NMR (400 MHz, CDCl3) 9.75 (d, J=2.8 Hz, 1H), 4.62 (dq, J=9.7, 6.0 Hz, 1H), 2.8-2.70 (m, 2H), 2.65-2.55 (m, 3H), 2.50 (d, J=7.2 Hz), 2.10 (ddd, J=13.2, 6.4, 3.0 Hz, 1H), 1.94 (ddd, J=13.6, 6.0, 3.0, 1H), 1.69 (dq, J=10.9 Hz, 3.00 Hz, 1H), 1.58-1.48 (m, 1H), 1.42-1.20 (m, 3H), 1 .33(d, J=6.4 Hz, 3H).
Step 10:
To a solution of the product of Step 9 (90 mg, 0.35 mmol) in MeOH (10 ml) (4:1 v/v) at 0xc2x0 C., excess NaBH4 was added and the mixture stirred for 15 min at 0xc2x0 C. The reaction was quenched with aq. NH4Cl (50 ml) and extracted with EtOAc (3xc3x9720 ml). The combined organic layer was washed with brine (50 ml), dried over MgSO4 and concentrated to provide the crude alcohol. A solution of the alcohol in MeOH-THF (6 ml, 1:1 v/v) was added to a flask containing excess Raney nickel which was washed with dioxane and THF. The suspension was heated at reflux for 3 h, cooled, filtered, concentrated and chromatographed with 25% EtOAc-hex to provide 54 mg (67%) of title compound as a resin. 1H NMR (400 MHz, CDCl3) 4.70 (dq, J=9.7, 5.9 Hz, 1H), 3.73 (dd, J=10.5, 3.4 Hz, 1H), 3.62 (dd, J=10.5, 7.6 Hz, 1H), 2.60-2.53 (m, 1H), 2.46 (ddd, J=9.6, 7.2, 5.2 Hz, 1H), 1.90 (ddd, J=13.5, 6.1, 3.1 Hz, 1H), 1.87-1.81 (m, 1H), 1.77 (br s, 1H), 1.66-1.59 (m, 1H), 1.50 (d, J=6.0 Hz, 3H), 1.48-1.36 (m, 2H), 1.25-1.14 (m, 2H), 0.93 (d, J=6.6 Hz, 3H), 0.78 (d, J=7.5 Hz, 3H) 13C NMR (100 MHz, CDCl3) 178.58, 77.63, 61.79, 45.10, 42.49, 39.37, 38.65, 33.44, 31.96, 21.39, 19.91, 19.74, 7.26. 
Step 1: 
Prepared according to the procedure described in Wang et. al. Tet. Lett, 41, (2000), p. 4335-4338.
Step 2:
To a solution of the product of Step 1 (20 g, 106 mmol) and Et3N (17.8 ml, 128 mmol, 1.2 eq.) in CH2Cl2 (300 ml) keptxcx9cxe2x88x9230xc2x0 C. was slowly added CH3SO2Cl (9.1 ml, 118 mmol, 1.1 eq.). The slurry was stirred for 1 h while it warmed up to 0xc2x0 C. The reaction mixture was diluted with aq. NaHCO3 (500 ml) and the organic layer was separated. The aqueous layer was extracted with Et2O (2xc3x97200 ml) and the combined organic layers was washed with aq. NaHCO3 (2xc3x97300 ml) and brine (300 ml). The solution was dried over MgSO4, filtered and evaporated to give the crude mesylate, which was used as such for the next step.
1H NMR: 8.67 (d, J=2.0 Hz, 1H), 7.89 (dd, J=8.4, 2.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 5.28 (s, 2H), 3.10 (s, 3H).
Step 3:
To a suspension of 60% NaH (8.5 g, 212 mmol 2.0 eq.) in THF (500 ml) at rt was added diethylphosphite (27.4 ml, 213 mmol, 2 eq,) drop by drop and the mixture was stirred for 1 h. To this cloudy solution was added a solution of the product of Step 2 in THF (125 ml) and the mixture was stirred at rt for 1 h. The reaction was quenched by the addition of H2O (500 ml), the THF was evaporated and the aq. layer was extracted with EtOAc (4xc3x97150 ml). The combined organic layers were washed with aq. K2CO3 (2xc3x97300 ml), brine (300 ml), dried over MgSO4, filtered, evaporated and the crude product was chromatographed with 5:95 CH3OHxe2x80x94CH2Cl2 to give 31.7 g (97%) of oil.
1H NMR: 8.59 (d, J=2.0 Hz,1H), 7.76 (dd, J=8.2, 2.1 Hz, 1H), 7.29 (dd, J=8.2, 2.2 Hz,1H), 4.12-4.05 (m, 4H), 3.36 (d, J=22.0 Hz, 2H), 1.27 (t, J=7.0 Hz, 6H) 
To a solution of the product of Preparation 3 (15 g, 49 mmol, 1.5 eq.) in THF (100 ml) at 0xc2x0 C. was added 1M LHMDS in THF (49 ml, 49 mmol, 1.5 eq.) and the solution was stirred for 30 min. To this was added Ti(O""Pr)4 (14.4 ml, 49 mmol, 1.5 eq.) followed by a solution of the product of Preparation 1 (7.3 g, 32 mmol) in THF (30 ml) and the mixture was stirred at rt for 45 min. The solution was diluted with aq. potassium sodium tartrate (300 ml) and the THF was evaporated. The slurry was extracted with EtOAc (4xc3x97100 ml) and the combined organic layer washed with brine (100 ml), dried over MgSO4, filtered, concentrated and the resultant crude product was chromatographed with 15:85 EtOAc-hexane to provide 11.8 g (96%) of foam.
1H NMR: 8.58 (d, J=2.4 Hz, 1H), 7.74 (dd, J=8.4, 2.8 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.55 (dd, J=15.6, 10.0 Hz, 1H), 6.45 (d, J=16.0 Hz, 1H), 4.75-4.68 (m, 1H), 2.69-2.56 (m, 2H), 2.32 (dt, J=10.1, 6.5 Hz, 1H), 1.98 (ddd, J=13.4, 6.6, 2.8 Hz, 1H), 1.67-1.59 (m, 1H), 1.47-1.39 (m, 2H), 1.37 (d, J=5.9 Hz, 3H), 1.31-1.20 (m, 2H), 0.98 (d, J=6.2 Hz, 3H), 0.73 (t, J=7.5 Hz, 3H) 
To a solution of the product of Preparation 4 (7.2 g, 19 mmol), in THF (100 ml) at xe2x88x9278xc2x0 C. was added 1M LHMDS in THF (23 ml, 23 mmol, 1.2 eq.). The solution was stirred for 30 min at xe2x88x9278xc2x0 C., 30 min at 0xc2x0 C. and cooled back to xe2x88x9278xc2x0 C. To this was added a solution of (1S)-(+)-(10-camphorsulfonyl)oxaziridine (6.0 g, 26 mmol, 1.4 eq.) in THF (50 ml) and the mixture was stirred for 1 h at xe2x88x9278xc2x0 C. and 1.5 h at 0xc2x0 C. To the solution was added aq. NH4Cl (300 ml), THF was evaporated and the aqueous layer was extracted with EtOAc (4xc3x97100 ml). The combined organic layer was washed with brine (100 ml), dried over MgSO4, filtered, concentrated and the crude product was chromatographed with 15:20:65 EtOAcxe2x80x94CH2Cl2-hex to provide 6.4 g (85%) of foam.
1H NMR: 8.56 (d, J=2.0 Hz, 1H), 7.72 (dd, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.56 (dd, J=15.6, 9.8 Hz, 1H), 6.48 (d, J=15.6 Hz, 1H), 4.62-4.55 (m, 1H), 3.72 (br s, 1H), 2.80-2.74 (m, 1H), 2.28 (dd, J=9.6, 5.6 Hz, 1H), 1.81-1.78 (m, 2H), 1.63-1.58 (m, 1H), 1.44-1.27 (m, 3H), 1.37 (d, J=6.0 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 0.73 (t, J=7.5 Hz, 3H) 
Step 1:
To a solution of (R)-(+)-3-butyn-2-ol (5 ml, 64 mmol) in CH2Cl2 (100 ml) at rt was added DMAP (780 mg, 6.4 mmol, 0.1 eq.), tert-butylchlorodiphenylsilane (17.4 ml, 67 mmol, 1.05 eq.) and Et3N (9.8 ml, 70 mmol, 1.1 eq.). The mixture was stirred overnight, diluted with Et2O (400 ml), washed with 1N HCl (2xc3x97200 ml), aq. NaHCO3 (200 ml), brine (200 ml), dried over MgSO4, filtered and evaporated to give xcx9c20 g of oil which was used as such for the next step.
Step 2:
To a solution of the product of Step 1 in THF (200 ml) at xe2x88x9278xc2x0 C. was added 2.5M BuLi in hexanes (30.4 ml, 76 mmol, 1.1 eq.), the solution was stirred for 1 h and solid paraformaldehyde (4.15 g, 138 mmol, 2.0 eq.) was added. The mixture was stirred for 15 min at xe2x88x9278xc2x0 C., 1 h at rt, then quenched with the addition of aq. NH4Cl (500 ml). The THF was evaporated and the aqueous layer was extracted with EtOAc (3xc3x97200 ml). The combined organic layers were washed with H2O (2xc3x97300 ml) and brine (300 ml), dried over MgSO4, filtered, evaporated and the crude was chromatographed with 10% EtOAc-hex to provide 16.5 g (71%) of resin.
1H NMR: 7.77-7.74 (m, 2H), 7.71-7.68 (m, 2H), 7.46-7.36 (m, 6H), 4.53 (tq, J=1.8, 6.5 Hz, 1H), 4.08 (dd, J=6.2, 1.8 Hz), 2.82 (d, J=6.4 Hz, 3H), 1.07 (s, 9H)